Microglia, the resident macrophages of the CNS, are implicated in many acute and chronic neurological diseases, including multiple sclerosis, trauma and stroke. While many laboratories are studying the role of activated microglia in CNS pathophysiology, the molecular mechanisms controlling the activation process of microglial are less understood. Recent progress in genetics has identified a new class of RNA molecules called microRNAs (miRNA) involved in gene regulation. miRNAs are single-stranded RNA molecules of ~22 nucleotides complementary to a site in the 3'untranslated region (UTR) of mRNAs. The annealing of the miRNA to the mRNA inhibits protein translation and sometimes facilitates cleavage of the mRNA. This regulation adds an unexpected layer of complexity to the classic linear concept of DNA mRNA protein. Fast paced progress in the last two years showed the importance of miRNA in regulating neuronal and immune functions. Despite these landmark advances, the functional role of miRNAs in microglial activation is currently unknown. We now hypothesize that miRNAs are an integral part of the microglial activation process and central in regulating downstream effector functions such as cytokine release. We propose to test this hypothesis with the following three aims: 1. Obtain a comprehensive picture of miRNA expression in microglial cells and their regulation by activation. 2. Identify the role of specific miRNAs in microglial physiology. 3. Identify the role of miR-155 in ischemic brain injury .The broad, long-term goal of this project is to understand the role of miRNAs in microglial cell activation. We believe that the molecular mechanisms identified through our experiments may reveal new approaches for therapeutic intervention in CNS injuries associated with microglial activation such as stroke. PUBLIC HEALTH RELEVANCE The broad, long-term goal of this project is to understand the role of miRNAs in the activation of microglial cells. We believe that the signal transduction mechanisms identified through our experiments may constitute new targets for therapeutic intervention in CNS injuries associated with microglial activation such as trauma, multiple sclerosis or stroke.